TY  - JOUR
AU  - Xu, Shihao
AU  - Chaudhary, Omkar
AU  - Rodríguez-Morales, Patricia
AU  - Sun, Xiaoli
AU  - Chen, Dan
AU  - Zappasodi, Roberta
AU  - Xu, Ziyan
AU  - Pinto, Antonio F M
AU  - Williams, April
AU  - Schulze, Isabell
AU  - Farsakoglu, Yagmur
AU  - Varanasi, Siva Karthik
AU  - Low, Jun Siong
AU  - Tang, Wenxi
AU  - Wang, Haiping
AU  - McDonald, Bryan
AU  - Tripple, Victoria
AU  - Downes, Michael
AU  - Evans, Ronald M
AU  - Abumrad, Nada A
AU  - Merghoub, Taha
AU  - Wolchok, Jedd D
AU  - Shokhirev, Maxim N
AU  - Ho, Ping-Chih
AU  - Witztum, Joseph L
AU  - Emu, Brinda
AU  - Cui, Guoliang
AU  - Kaech, Susan M
TI  - Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.
JO  - Immunity
VL  - 54
IS  - 7
SN  - 1074-7613
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2021-01275
SP  - 1561-1577.e7
PY  - 2021
N1  - 2021 Jul 13;54(7):1561-1577.e7
AB  - A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36-/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
KW  - CD36 (Other)
KW  - CD8(+) T cells (Other)
KW  - lipid peroxidation (Other)
KW  - oxidized lipids (Other)
KW  - tumor microenvironment (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34102100
DO  - DOI:10.1016/j.immuni.2021.05.003
UR  - https://inrepo02.dkfz.de/record/169133
ER  -